Mechanisms of Alcohol and Polyphenol Cardioprotection

描述（由申请人提供）：流行病学研究表明，轻度至中度酒精饮料或红葡萄酒饮用者（1-4杯/天）的死亡率（20-40%）明显低于不饮酒者或重度饮酒者，因为总体冠心病相关死亡率风险降低。酒精或红酒成分（主要多酚）影响多种可能提供心血管疾病保护的生物功能，然而，这种心脏保护的分子和细胞机制仍然不明确和不清楚。这个跨学科项目的综合研究主题是确定和定义适度饮酒或红酒多酚影响系统循环成分（血管/成分，ECs）和心肌功能（心肌细胞）的分子调控机制，这些机制有助于适度饮酒或红酒对心脏的保护作用。结合基因缺陷小鼠模型的体内研究（包括PAs -/-， Pmg -/-, PAI-1 -/-, eNOS -/-, iNOS -/-, SOD -/-, apoE-/-）和体外培养细胞（人/小鼠ECs，肌细胞）的研究将通过四个综合研究项目来解释这些保护机制，由三个核心单位（管理，组织培养/质粒和动物poioanalysis）支持。项目1将通过EC纤溶蛋白（PAs, PARs, pmgr）功能、表达和基因转录调节EC纤溶蛋白增加的机制来研究保护作用。项目2将通过EC PAI-1功能、表达和基因转录调控的EC纤维蛋白溶解增加机制来研究保护作用。项目3将通过EC eNOS/SOD表达和eNOS基因转录调控的NO生物利用度增加和血管功能改变机制来研究保护作用。项目4将研究心肌细胞NO生成/iNOS表达的增加，以及通过NO依赖性调节心脏线粒体呼吸功能对小鼠心脏缺血-再灌注的保护作用。从这些研究项目中收集到的集体结果将为我们对这些多种乙醇/多酚诱导的心脏保护机制的个体、组合或协同作用的理解提供重要的新见解，这些机制是降低血栓形成、动脉粥样硬化/冠心病和心肌梗死的动脉粥样硬化血栓后果风险的基础和贡献，从而降低冠心病和冠心病相关死亡率。

DESCRIPTION (provided by applicant): Epidemiological studies have shown that light-to-moderate drinkers of alcoholic beverages or red wine (1-4 drinks/day) have significantly lower mortality rates (20-40%) than nondrinkers or heavier drinkers, due to reduced risk for overall CHD-related mortality. Alcohol or red wine components (principal polyphenols) affect a diverse number of biological functions that may afford cardiovascular disease protective benefits, however, the molecular and cellular mechanisms underlying this cardioprotection remain poorly defined and understood. The integrating research theme of this inter-disciplinary Program Project Grant is to identify and define the molecular regulatory mechanisms by which moderate alcohol- or red wine polyphenols affect systemic circulatory components (blood vessels/components, ECs) and myocardial function (cardiomyocytes) that contribute to the cardioprotective benefits attributed to moderate alcohol or red wine consumption. A combination of both in vivo studies with genetically deficient murine models (including PAs -/-, Pmg -/-, PAI-1 -/-, eNOS -/-, iNOS -/-, SOD -/-, apoE-/-) and in vitro studies with cultured cells (human/mouse ECs, myocytes) will be used to decipher some of these protective mechanisms through four integrated research projects, supported by three core units (administrative, tissue culture/plasmid and animalPoioanalysis). Project 1 will study protection through mechanisms of increased EC fibrinolysis, regulated by EC fibrinolytic protein (PAs, PARs, PmgRs) function, expression and gene transcription. Project 2 will study protection through mechanisms of increased EC fibrinolysis, regulated by EC PAI-1 function, expression and gene transcription. Project 3 will study protection through mechanisms of increased NO bioavailability and altered vascular function, regulated by EC eNOS/SOD expression and eNOS gene transcription. Project 4 will study increased NO production/iNOS expression in cardiomyocytes and protection of the mouse heart from ischemic-repeffusion through NO-dependent modulation of cardiac mitochondrial respiratory function. The collective results gleaned from these research projects will provide significant new insights into our understanding of the individual, combined or synergistic roles of these multiple ethanol- /polyphenol-induced cardioprotective mechanisms that underlie and contribute to the decreased risk for thrombosis, atherosclerosis/CHD and the atherothrombotic consequence of MI, thereby reducing overall CHD and CHD-related mortality.